N-Bromosuccinimide (NBS) is a well known synthetic organic reagent which is useful in bromination and/or oxidation of a wide variety organic moieties under a wide variety of reaction conditions. A review of NBS chemistry is found in J.S. Pizey, Synthetic Reazents, vol. 2 (John Wiley, New York, 1974) at pages 1-63. While NBS brominations of aromatic moieties have been performed in polar and non-polar organic solvents and in aqueous acidic solution, there have been no reports of NBS brominations utilizing aqueous alkali solutions as the reaction medium. Utilization of such a basic medium has the advantage in that hydrogen bromide, generated in the reaction, is scavenged by the solvent, thereby reducing the possible side reactions associated with its presence in solution. Multiple brominations are also not observed.
Dibromodimethylhydantoin (DBDMH), while not as widely employed as NBS, is a versatile organic reagent (for a review see: Reed, R. A., Chem. Prod., 23, 299 (1960)). It offers the advantage of being more stable and less costly on a bromine equivalent basis than NBS. Previous disclosed brominations of aromatic substrated using DBDMH were run in refluxing CCl.sub.4 or CHCl.sub.3. DBDMH is also used as a pool disinfectant.
Remoxipride I ((S)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenzamide), shown below, is a known antipsychotic agent (U.S. Pat. No. 4,232,037). Preparation of remoxipride typically involves a convergent synthesis wherein a suitably activated 3-bromo-2,6-dimethoxybenzoic acid II is coupled with the enantiomerically pure aminomethyl pyrrolidine III. ##STR1##
Preparation of Intermediate IVa the precursor of compound II typically involves bromination of commercially available 2,6-dimethoxybenzoic acid employing bromine and dioxane as shown below. ##STR2##
Although good yields of the Intermediate IVa are obtained from the reaction, several impurities, shown below, result from the further reaction of the product and bromine and/or the hydrogen bromide generated in the reaction. ##STR3##